Osteoarthritis (“OA”), the most common form of arthritis, is a type of arthritis that is characterized by degenerative (gradual deterioration of joint) or abnormal changes in bone, cartilage, and synovium of the joints. OA is often characterized by a progressive wearing down of opposing joint surfaces accompanied at times by inflammation resulting in pain, swelling, and stiffness for the patient. OA can occur in one or more joints following trauma to the joint, following an infection of the joint, or simply as a result of aging. Furthermore, there is emerging evidence that abnormal anatomy may contribute to early development of OA. In the US alone, over 25 million people are estimated to have radiographic OA of the knee, with 16 million of those suffering from symptomatic OA. The prevalence of OA is increasing rapidly, in part due to an aging population that is more active, as well as an increasingly obese general population.
Treatment of OA generally involves a combination of exercise or physical therapy, lifestyle modification, and analgesics. Acetaminophen is typically the first line of treatment for OA. For mild to moderate symptoms, effectiveness is similar to non-steroidal anti-inflammatory drugs (“NSAIDs”), such as ibuprofen. For more severe symptoms, NSAIDs may be more effective. However, while more effective, NSAIDs in severe cases are associated with greater side effects such as gastrointestinal bleeding and renal complications. Another class of NSAIDs, COX-2 selective inhibitors (such as Celecoxib), is equally effective as NSAIDs but no safer in terms of side effects. There are several NSAIDs available for topical use, including diclofenac. Typically, they have less systemic side-effects than oral administration and at least some therapeutic effects. While opioid analgesics, such as morphine and fentanyl, improve pain, this benefit is outweighed by frequent adverse events and thus they are not routinely used.
Intra-articular steroid injections are also used in the treatment of OA, and they are very effective at providing pain relief. However, the durability of the pain relief is limited to 4-6 weeks and there are adverse effects that may include collateral cartilage damage. If pain becomes debilitating, joint replacement surgery may be used to improve mobility and quality of life. There is no proven treatment to slow or reverse the disease.
For patients who do not get adequate pain relief from simple pain relievers, like acetaminophen or from exercise and physical therapy, intra-articular injections of hyaluronic acid (HA) provide another treatment option to address symptomatic pain and delay the need for a total joint replacement surgery. It is known that the concentration of native HA is deficient in individuals suffering from OA and therefore joint injections of exogenous HA is believed to replenish these molecules and restore the viscoelastic properties of synovial fluid. It is this property that is responsible for lubricating and cushioning the joints. There is also evidence that HA has biological activity through binding to cell surface receptors and may have a role in mitigating inflammation. Independent of the mechanism of action, pain relief is observed for about six months following a treatment course. A treatment course for HA products on the US market can range from single injection product to others that require 3 to 5 weekly injections to attain this durability of pain relief. In using intra-articular injections, it is well-known that a neutral pH and an isotonic solution are preferred to avoid pain with injection and joint or tissue damage. The desire for a neutral and isotonic solution can limit the type and concentration of drugs that can be injected.
While the above therapies can provide at least a partial relief of OA pain, there are no approved therapies that can slow or halt the progression of the disease in humans. Accordingly, there remains a need for improved methods and compositions for treating OA in joints, and to address the pain and structural degeneration associated with OA.